The underlying mechanism of delayed cell death in the spinal cord after injury is poorly understood. Secondary injury has been proposed to cause progressive cell death and tissue loss after the initial physical insult. Post-traumatic inflammatory reaction may play an important role in the secondary injury. Cardinal features of an acute inflammatory response have been demonstrated in the injured cord for at least several days after the traumatic insult. Inflammatory processes in the CNS have a predilection for the white matter. White matter lesions, including demyelination, are the major cause of disability after SCI. Cytokines are inflammatory mediators expressed by inflammatory cells. Cytokines, particularly tumor necrosis factor-alpha (TNF), have been shown to cause apoptosis in oligodendrocytes (ODCs) in vitro and demyelination in vivo. We will explore a possible pathogenic role of TNF-alpha in ODC apoptosis in the context of a post-traumatic inflammatory reaction. A simplified scheme is shown below: This project will focus mainly on the role of TNF-alpha in ODC apoptosis after SCI. In vivo studies, using rat and transgenic mouse SCI models, and in vitro studies, using ODC cultures, will be conducted to test the hypothesis that TNF-alpha expression contributes, at least partially, to ODC apoptosis after SCI. We will also test the hypothesis that apoptotic ODC cell death and subsequent demyelination is reduced and functional outcome is improved by interventions that effectively inhibit TNF-alpha expression or block its actions. This project will also serve as a platform for developing new therapeutic regimens, including combination strategies directed at different steps in the post-traumatic inflammatory cascade. The ultimate goal of this project is to enhance functional recovery after SCI through a reduction in ODC death.